MOLECULAR TAXONOMY OF LUNG AND ESOPHAGEAL CANCERS. 1. Internal Exposome: African Americans have a higher risk of developing lung cancer than European Americans. We hypothesized that variations in serum cytokine levels exist between African Americans and European Americans, and increased circulating cytokine levels contribute to lung cancer differently in the two races. Differences in 10 serum cytokine levels, IL1 beta, IL4, IL5, IL6, IL8, IL10, IL12, granulocyte macrophage colony-stimulating factor, IFN gamma, and TNF alpha, between 170 African-American and 296 European-American controls from the National Cancer Institute-Maryland (NCI-MD) case-control study were assessed. Statistically significant results were replicated in the prospective Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and the Wayne State University Karmanos Cancer Institute case-control study. Six cytokines, IL4, IL5, IL8, IL10, IFNgamma, and TNFalpha, were significantly higher among European-American as compared with African-American controls. Elevated IL6 and IL8 levels were associated with lung cancer among both races in all 3 studies. Elevated IL1beta, IL10, and TNF alpha levels were associated with lung cancer only among African Americans. The association between elevated TNF alpha levels and lung cancer among European Americans was significant after adjustment for additional factors. Serum cytokine levels vary by race and might contribute to lung cancer differently between African Americans and European Americans. (Pine et al, 2016). External Exposome: Mutation analysis of limited numbers of genes has indicated that colorectal tumors that develop in patients with IBD differ from those of patients without IBD. Whole-exome sequencing analyses were performed on microdissected colorectal tumor and matched non-neoplastic tissues from 31 patients with IBD and colorectal cancer (15 with ulcerative colitis, 14 with Crohn's disease, and 2 with indeterminate colitis). The prevalence of mutations in sporadic colorectal tumors was obtained from previously published studies. Two specimens had somatic mutations in the DNA proofreading or mismatch repair genes POLE, MLH1, and MSH6 and the tumor cells had a hypermutable phenotype. The remaining tumors had, on average, 71 alterations per sample. TP53 was the most commonly mutated gene, with prevalence similar to that of sporadic colorectal tumors. However, tumors from the patients with IBD had a different mutation spectrum. APC and KRAS were mutated at significantly lower rates in tumors from patients with IBD than in sporadic colorectal tumors. Several genes were mutated more frequently or uniquely in tumors from patients with IBD, including SOX9 and EP300, NRG1, and IL16. Our study also revealed recurrent mutations in components of the Rho and Rac GTPase network, indicating a role for noncanonical WNT signaling in development of colorectal tumors in patients with IBD. Colorectal tumors that develop in patients with IBD have distinct genetic features from sporadic colorectal tumors. (Robles et al 2016). 2. Genome. Small cell lung cancer (SCLC) is the most aggressive type of lung cancer. Only 15% of SCLC patients survive beyond 2 years after diagnosis. In collaboration with J. Yokota, exome sequencing was performed in primary and metastatic tumors from 38 patients with SCLC in order to identify genes frequently mutated and expressed in SCLCs that could be targetable for therapy. Expression of mutant alleles was verified by RNA sequencing. Overall, our study indicates that, in addition to previously found TP53, RB1 and PTEN, TMEM132D, SPTA1 and VPS13B could be also involved in SCLC development, with the products from their mutated alleles being potential therapeutic targets in SCLC patients (Iwakawa, 2015). 3. Epigenome. Genome-wide screening of DNA methylation and pyrosequencing analysis of HOXA9 promoter methylation were performed in two independently collected cohorts of stage I lung adenocarcinoma (ADC). Promoters of genes marked by polycomb in embryonic stem cells were methylated de novo in tumors and identified patients with poor prognosis. High HOXA9 promoter methylation was associated with worse cancer-specific survival (hazard ratio [HR], 2.6; p = 0.02) and recurrence-free survival (HR, 3.0; p = 0.01), and identified high-risk patients in stratified analysis of stages IA and IB (Robles, 2015). 4. Metabolome. In collaboration with Frank Gonzalez, we identified diagnostic and prognostic urine metabolomic biomarkers (Mathe, 2014). We have evaluated their utility in pre-diagnostic samples from the well-characterized prospective Southern Community Cohort Study (SCCS), comprising 178 lung cancer cases and 351 controls. In the SCCS cohort, creatine riboside and N-acetylneuraminic acid (NANA) were identified as risk biomarkers (Haznadar et al, 2016). To evaluate if these biomarkers may complement LDCT screening, we will measure them in the urine of 307 cases and 614 controls from the National Lung Screening Trial (NLST) and evaluate if they can distinguish benign from malignant nodules with a higher specificity than LDCT alone. We have integrated the lung cancer molecular markers to generate classifiers predictive of disease outcome. The prognostic value of HOXA9 promoter methylation alone and in combination with mRNA and miRNA biomarkers was assessed in two independent cohorts of stage I lung ADC. Four protein-coding gene, miR-21 expression, and HOXA9 promoter methylation were each independently associated with outcome, and when combined, identified high-risk, stage I patients (HR, 10.2; p = 3x10). We propose that a prognostic classifier comprising three types of genomic and epigenomic data may help guide the postoperative management of stage I lung ADC patients at high risk of recurrence (Robles et al, 2015). MOLECULAR TAXONOMY OF COLORECTAL CANCER (CRC). The expression of miR-34a/b/c was found to be significantly increased in tumors compared to adjacent noncancerous tissues from 159 American and 113 Chinese colon cancer patients, counter to the proposed tumor suppressor role for these miRNAs. Increased miR-34b/c was associated with more advanced tumors and poor cancer-specific mortality. Expression of miR-34 family was associated with TP53 transcriptional activity, consistent with the proposed regulation of miR-34a/b/c by TP53, but not with TP53 mutation status. Expression of miR-34b/c in cancer stroma was associated with poor prognosis in CRC (Hiyoshi, 2015). Distant metastasis is the major cause of mortality in CRC. CRC metastasis-specific miRNAs were determined in pairs of primary CRC (pCRC) and Liver Metastasis (LM). Twenty-three miRNAs were identified that were differentially expressed between pCRC and LM. A metastasis-specific miRNA signature and novel tissue- and serum-based CRC metastasis-specific miRNA biomarkers were discovered and validated. These unique miRNAs may be clinically applicable to predict prognosis and distant metastasis in CRC (Hur, 2015). CRC represents a group of histopathologically and molecularly heterogeneous diseases, which may contain signet-ring cell and/or mucinous components with unknown prognostic significance. In 1,336 rectal and colon cancer patients we found that even a minor (50 % or less) signet-ring cell component, but not mucinous component, was associated with higher patient mortality, independent of other molecular and clinicopathological features (Inamura, 2015).